Gelatin capsules are widely used in the pharmaceutical industry for oral administration of a variety of active agents. In general, there are two types of gelatin capsules. Soft gelatin capsules are used to contain semisolids, liquids and pastes, and hard gelatin capsules are used to contain powders and granules. Soft gelatin capsules suffer from the disadvantages that they require significantly more gelatin for encapsulation of a given dose of pharmaceutically active compound than hard gelatin capsules, and that they are typically made and filled by contract manufacturers. Hard gelatin capsules are supplied by specialist manufacturers for filling by the producer of the material to be encapsulated. Quality control considerations favor capsule filling by the producer of the filling material and considerable increases in the price of gelatin favor the use of hard gelatin capsules. However, if hard gelatin capsules are used to contain materials other than powders and granules, there have been problems of leaking of capsule contents in handling. The leaking can only be overcome by time-consuming and cumbersome operations such as banding of the capsule after filling. Such operations add greatly to production costs.
Recently, a capsule filling medium which is semisolid, liquid or paste-like in nature has been developed which can be readily introduced into hard gelatin capsules without the expected problems of leakage. This thixotropic medium can be introduced into the capsule in a state of low viscosity and, once in the capsule, the medium assumes a relatively high viscosity, thereby reducing the tendancy of the medium to leak from the capsule. These formulations are described in detail in U.K. Patent No. 1,590,864.
The use of semi-solid matrix formulations permits the control of the rate of release of the active agent in the formulation by altering the hydrophilic-lipophilic balance of the matrix. Matrices of high lipophilicity having a high melting point erode slowly, thereby delaying the release of the active agent from the matrix. In contrast, matrices that are highly hydrophilic and have melting points at or near about 37.degree. C. will dissolve rapidly.
The present invention provides a sustained release pharmaceutical formulation in capsule unit dosage form comprising a gelatin capsule containing a semi-solid matrix comprising a pharmaceutically active agent, a pharmaceutically acceptable hydrophobic carrier matrix and a hydrophilic substance capable of providing diffusion channels into the hydrophobic carrier. The present formulation contains a non-dispersing, slow eroding hydrophobic matrix having a melting point greater than about 37.degree. C. The hydrophobic nature of the matrix allows the formulation to retain its shape and physical integrity. In the absence of the hydrophilic additive the active agent is very slowly and incompletely released from the formulation. When the hydrophilic substance is incorporated into a formulation of the invention, water penetration into the formulation is promoted, thereby providing sustained release of the active agent. The hydrophilic additive absorbs water and causes the formulation to swell. Formulations of the invention containing a hydrophilic additive cause the active agent to be released more completely and over a more prolonged period of time.